Four‐Step Synthesis of (−)‐4‐epi‐Presilphiperfolan‐8α‐ol by Intramolecular Iron Hydride Atom Transfer‐Mediated Ketone‐Alkene Coupling and Studies to Accesstrans‐Hydrindanols with a Botryane Scaffold

Abstract

From an (R)‐(+)‐pulegone‐derived building block that incorporates the stereo‐defined tertiary carbon bearing a methyl group, as found in the targeted sesquiterpenoid, a four‐step synthesis of (−)‐4‐epi‐presilphiperfolan‐8‐α‐ol was achieved. The key processes involved are a ring‐closing metathesis leading to a bridged alkene‐tethered ketone and its subsequent FeIII‐mediated metal‐hydride atom transfer (MHAT) transannular cyclization. This synthetic method, implying an irreversible addition of a carbon‐centered radical upon a ketone by means of a hydrogen atom transfer upon the alkoxy radical intermediate, was also applied in the synthesis of trans‐fused hydrindanols structurally related to botrydial compounds.

Dual‐Catalysed Intermolecular Reductive Coupling of Dienes and Ketones**

“…We became interested in developing a solution to this problem using metal‐catalysed hydrogen‐atom transfer (MHAT) catalysis [23–26] . Previous methods have been reported in this area by Bradshaw and Bonjoch which rely on iron catalysis to couple olefins and carbonyl compounds [27–31] . However, the intermolecular examples are restricted to aldehyde carbonyl groups owing to the propensity of the alkoxy radical intermediate from ketones to undergo reversible β‐fragmentation and revert to the more stable C‐centred radical [32–35] .…”

“…[23][24][25][26] Previous methods have been reported in this area by Bradshaw and Bonjoch which rely on iron catalysis to couple olefins and carbonyl compounds. [27][28][29][30][31] However, the intermolecular examples are restricted to aldehyde carbonyl groups owing to the propensity of the alkoxy radical intermediate from ketones to undergo reversible β-fragmentation and revert to the more stable Ccentred radical. [32][33][34][35] Shenvi and co-workers have reported an alternative approach which proceeds through transmetallation to chromium to generate an anion-equivalent species.…”

Dual‐katalysierte intermolekulare reduktive Kopplung von Dienen und Ketonen**

“…Wir interessierten uns für die Entwicklung einer Lösung dieses Problems durch metallkatalysierten Wasserstoff‐Atom‐Transfer (MHAT) [23–26] . Bradshaw und Bonjoch berichteten über frühere Methoden auf diesem Gebiet, die sich auf die Eisenkatalyse stützen, um Olefine und Carbonylverbindungen zu koppeln [27–31] . Die intermolekularen Beispiele beschränken sich jedoch auf Aldehyd‐Carbonylverbindungen, da das Alkoxy‐Radikal‐Zwischenprodukt aus dem Keton zu reversibler β‐Fragmentierung und zur Umwandlung in das stabilere C‐zentrierte Radikal tendiert [32–35] .…”

“…[23][24][25][26] Bradshaw und Bonjoch berichteten über frühere Methoden auf diesem Gebiet, die sich auf die Eisenkatalyse stützen, um Olefine und Carbonylverbindungen zu koppeln. [27][28][29][30][31] Die intermolekularen Beispiele beschränken sich jedoch auf Aldehyd-Carbonylverbindungen, da das Alkoxy-Radikal-Zwischenprodukt aus dem Keton zu reversibler β-Fragmentierung und zur Umwandlung in das stabilere C-zentrierte Radikal tendiert. [32][33][34][35] Shenvi und Mitarbeiter haben über einen alternativen Ansatz berichtet, bei dem durch Transmetallierung zu Chrom eine Anionen äquivalente Spezies erzeugt wird, [36] die jedoch, ähnlich wie bei den zuvor genannten Beispielen, nur mit Aldehyden und Aldiminen reagieren kann.…”

Isocyanides as Acceptor Groups in MHAT Reactions with Unactivated Alkenes

“… 2 Key advantages of using alkenes as proradicals include their general ubiquity as chemical feedstocks, their stability in synthetic sequences, and their specific reaction profiles. Additionally, the novel disconnection possibilities arising from the use of alkenes as radical precursors has led to MHAT reactions making significant inroads into the field of total synthesis, 3 a trend likely to increase as more acceptor groups become available in this burgeoning research area. Acceptor groups currently used in MHAT C–C coupling reactions include electron-deficient alkenes, 4 sulfonylhydrazones derived from formaldehyde, 5 nitriles, 6 pyridine salts, 7 imines, 8 N -sulfinylimines, 9 acylsilanes, 10 alkynyl bromides, 11 β-nitroalkenes, 12 and difluoroalkenes.…”